A team of researchers from the Italian Institute of Technology - IIT and Sapienza University of Rome led by Irene Bozzoni, coordinator of the Non-coding RNAs in Physiology and Pathology laboratory, has discovered a new correlation between circular RNA molecules and the paediatric tumour rhabdomyosarcoma. The findings, published in the journal Nature Communications, represent an important contribution to the development of innovative therapeutic approaches

RNA represents, along with DNA and proteins, one of the main components the cell has at its disposal to respond effectively to the continuous stimuli it is subjected to. RNA has recently gained popularity even among the lay public as it was the technology adopted for the Covid-19 vaccine, an indispensable tool in preventing contagions due to the now notorious SARS-CoV-2 virus.

There are classes of RNAs that differ in structure and function. Among them is that of circular RNAs (circRNAs), so called because they have a closed, ring-like structure, which provides certain advantages, first and foremost, high stability compared to linear RNAs.

These represent a newly rediscovered class as, until about ten years ago, their study was severely limited by the absence of appropriate techniques for their identification in biological samples.

CircRNAs perform multiple functions within the cell and are therefore involved in fundamental physiological processes and the development of various diseases, including cancer.

A group of researchers from Sapienza University and the Italian Institute of Technology has studied the role of circular RNAs in rhabdomyosarcoma, a highly diffuse paediatric tumour classified among the so-called soft tissue sarcomas that originates from stem cells from which numerous tissues, including skeletal muscle, derive. For this reason, this tumour can occur at any site where muscles are present.

The authors of the study, published in Nature Communications, characterised circular RNA expression in this tumour, finding that some show higher levels than in the healthy context.

Looking for the mechanisms behind this effect, the authors found that a group of proteins that operate the deposition and reading of N6-methyladenosine (m6A) on RNA would be responsible. These proteins show markedly high levels in both biopsies and rhabdomyosarcoma lines. Furthermore, the study showed that increased m6A promotes rhabdomyosarcoma tumour cells' proliferation and metastatic activity. This effect could be partly attributable to the circular RNA molecules directly regulated by this modification.

The helicase DDX5, a protein known for its multiple roles in RNA metabolism, is also said to be involved in the process. DDX5 can stimulate the production of a class of circRNAs and interacts with YTHDC1. This protein binds m6A-containing RNAs and has previously been described by the same Sapienza group as a promoter of the production of a class of circRNAs.

The results of this study, funded by the AIRC Foundation, are a valuable contribution to understanding the molecular mechanisms underlying this tumour and developing new therapeutic approaches where traditional strategies have failed.

References:

The m6A reader YTHDC1 and the RNA helicase DDX5 control the production of rhabdomyosarcoma-enriched circRNAs – Dario Dattilo, Gaia Di Timoteo, Adriano Setti, Andrea Giuliani, Giovanna Peruzzi, Manuel Beltran Nebot, Alvaro Centrón-Broco, Davide Mariani, Chiara Mozzetta and Irene Bozzoni – Nature Communications 2023. doi: 10.1038/s41467-023-37578-7 https://www.nature.com/articles/s41467-023-37578-7

Further Information

Irene Bozzoni 
Department of Biology and Biotechnology "Charles Darwin "
irene.bozzoni@uniroma1.it